Aging is a complex biological process, involving all tissues of the body and their interactions through metabolism and genetic biology. It has been known for some time that reducing caloric intake can promote extension of median and maximal lifespan across a broad range of eukaryotic organisms from yeast, through insects, worms, rodents and nonhuman primates. There have been numerous controlled and uncontrolled studies of the effects of caloric restriction on surrogate biomarkers of aging lasting up to six months, but the effects of longer term calorie restriction notably have been absent until the inception of the CALERIE study. The CALERIE study was designed to assess the effects of two years of sustained and significant caloric restriction without enforced changes of dietary composition in human subjects in a randomized controlled trial. The duration of the intervention and the randomized nature of the treatment assignment had never previously been attempted in a human study. These factors, combined with the substantial size of the study, the careful attention to detail in the physiologic assessments, careful collection of extensive clinical data, and the extensive biorepository of samples collected from study participants, make the biorepository an invaluable resource for the investigation of the systematic molecular biological effects of medium term caloric restriction in human subjects. With this award, we will support the following projects for five years: maintenance of the data repository at Duke University, maintenance of the biorepository at the University of Vermont, the ability to link clinical data with biological samples, and the committee of CALERIE investigators who steward use of the samples. This repository will provide access to collected data and samples to present and future investigators investigating caloric restriction in humans. In addition, we will conduct preliminary systems biological investigations of the effects of caloric restriction using the biorepository samples. The Specific Aims are: 1) Maintenance of the CALERIE Data Repository and Biological Sample Repository; 2) Stewardship of applications for use of the CALERIE Sample Repository; 3) Address secondary questions regarding the biology of calorie restriction in humans. of current CALERIE data; 4) Curation of the CALERIE Database with molecular studies to promote a systems biology approach to the understanding of calorie restriction in humans. At the end of this funding period we will have available a rich biological and clinical data repository available to the scientific community for the investigation of innumerable hypotheses about the role of calorie restriction on the human aging biology.